CN103709194A - Preparation method of optically active hydroxyl protected aliphatic phosphate ester - Google Patents
Preparation method of optically active hydroxyl protected aliphatic phosphate ester Download PDFInfo
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- CN103709194A CN103709194A CN201410004195.7A CN201410004195A CN103709194A CN 103709194 A CN103709194 A CN 103709194A CN 201410004195 A CN201410004195 A CN 201410004195A CN 103709194 A CN103709194 A CN 103709194A
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Abstract
The invention relates to a preparation method of optically active hydroxyl protected aliphatic phosphate ester. The method can efficiently synthesize a side chain or a precursor of Treprostinil for treating pulmonary hypertension, and provides a brand new synthetic route and a synthetic strategy. Alcohol with double bonds at the optically active end is subjected to free radical addition reaction catalyzed by benzoyl peroxide to obtain the product precursor, and furthermore, different protective strategies can be adopted for the hydroxyl, so that the target compound can be prepared; the hydroxyl can be firstly protected and then phosphate ester and double bonds are subjected to addition reaction for preparing the optically active hydroxyl protected aliphatic phosphate ester. The optically active hydroxyl protected aliphatic phosphate ester can be used for preparing Treprostinil for treating pulmonary hypertension.
Description
Technical field
The present invention relates to the synthetic of a kind of protected phosphoric acid ester of optically active hydroxyl that can be used for preparing Pulmonary Hypertension new drug Treprostinil.
Background technology
Prostacyclin (prostaglin X) continuous intravenous injection is the standard care scheme of current clinical lung arterial hypertension.But the serious adverse reaction that intravenous injection may cause impels people to carry out the research and development of new drug and new preparation.Prostacyclin analogs Treprostinil can effectively treat pulmonary hypertension, comprises the treatment of primary and condary pulmonary hypertension.Its curative effect and prostaglin X are similar, can be used as the alternative medication of used for intravenous injection prostacyclin, and combine with warfarin and use warfarin pharmacokinetics and a few nothing impacts of pharmacodynamics.
In the building-up process of Ttreprostinil, relate to the synthetic of a kind of long-chain chiral alcohol side chain, concrete synthetic method only has minority bibliographical information bibliographical information (EP0159784, JP1985208936, US4668814A, US4683330.), its synthetic route is long, raw material reagent is not easy to obtain, the middle asymmetric epoxidation reaction that also relates to a step noble metal catalysis, totally with high costs, concrete route is as follows:
The method meaning of therefore inventing a kind of synthetic such side chain is fast and efficiently very great.
Summary of the invention
Technical problem to be solved by this invention is to overcome the deficiencies in the prior art, and a kind of synthetic method that is specially adapted to the phosphoric acid ester of optically active hydroxyl protection prepared by Pulmonary Hypertension new drug Treprostinil side chain is provided.
For solving above technical problem, one aspect of the present invention provides a kind of preparation method of aliphatic phosphate ester of optically active hydroxyl protection, comprises successively step:
(a) addition of phosphoric acid ester unsaturated link(age): phosphoric acid ester is carried out addition to the unsaturated link(age) of compound 2 under the effect of catalyzer, obtains product 3,
(b) to the hydroxyl of product 3, take multiple different protection strategy to protect, obtain the target compound 1 identical with product 3 skeletons,
The present invention provides the preparation method of the aliphatic phosphate ester of another optically active hydroxyl protection on the other hand, in turn includes the following steps:
(a) hydroxyl of compound 2 is protected, is obtained compound 4,
(b) further the carrying out addition reaction with phosphoric acid ester containing the compound 4 of unsaturated link(age) and obtain target compound 1 of hydroxyl protection,
In a particular instance, above-mentioned preparation method's starting raw material is that end is with the chiral alcohol of the S-configuration of two keys.
Preferably, aforesaid compound 2 or the contained unsaturated link(age) of compound 4 are two keys, and phosphoric acid ester comprises benzoyl peroxide, dilauroyl peroxide to the addition reaction of two keys catalyzer used, di-tert-butyl peroxide or dicumyl peroxide, the 0.05-0.3 equivalent that consumption is reaction substrate.
Preferably, phosphoric acid ester is dimethylphosphite to the addition reaction of two keys phosphoric acid ester used, diethyl phosphoric acid or diphenylphosphine oxygen or analogue.
Preferably, phosphoric acid ester adopts solvent Isosorbide-5-Nitrae-dioxane, DMF or normal heptane to the addition reaction of two keys, and preferred solvent is Isosorbide-5-Nitrae-dioxane.
Preferably, phosphoric acid ester comprises and is heated to 50 ℃-100 ℃ the reaction conditions of the addition reaction of two keys.
Preferably, the protection strategy that the protection of hydroxyl is adopted, comprises by silicon ether, ether, and ester or carbonic ether are protected.Particularly, the protective reaction to hydroxyl, when protecting group is TESCl, the condition of reaction be take imidazoles as alkali, and DMF is solvent; When blocking group is THP, catalyzer is I
2, methylene dichloride is solvent, DHP consumption is at 1-10; When protecting group is Cbz, preferred alkali is alkaline carbonate.
In a particular instance, the protective reaction to hydroxyl, protecting group is Cbz, under alkali exists with benzyl halide reaction.Enforcement due to technique scheme, the present invention compared with prior art tool has the following advantages: the preparation method who the invention provides the aliphatic phosphate ester of optically active long-chain, by the chiral alcohol with terminal olefinic link, under the effect of initiator, phosphoric acid ester is optionally carried out addition to two keys, obtain optically active phosphate compound, then hydroxyl is protected, obtain the phosphate compound by multiple different protecting group protections; Or first hydroxyl is protected, and then reacted with phosphoric acid ester, obtain optically active phosphate compound.Preparation method fast, efficient, cost is low, is specially adapted to the preparation of Pulmonary Hypertension new drug Treprostinil side chain.
Embodiment
The present invention relates to a kind of preparation method of aliphatic phosphate ester of optically active hydroxyl protection, this preparation method can be undertaken by following two kinds of modes, that is:
First phosphoric acid ester and two key carry out carrying out the protection of hydroxyl after addition again, finally obtain target compound 1, as follows:
Also after can first protecting hydroxyl, reaction finally obtains target compound 1 with phosphoric acid ester again, as follows:
Below in conjunction with specific embodiment, the present invention is described further, but the invention is not restricted to following examples.
Embodiment 1
In Isosorbide-5-Nitrae-dioxane (10vol) solution of compound 2 (1eq), add dimethylphosphite (3eq) and benzoyl peroxide (0.3eq).System is heated to react 1-2h under 80 ℃ of conditions, and gas phase monitoring has been reacted.In reaction, add water (100mL), EA (100mL*4) extraction.Organic phase is used respectively saturated NH
4cl (100mL), saturated NaHCO
3(100mL), Brine (100mL) washing once.Dried over mgso, filtration is spin-dried for, and the product 3 obtaining is directly used in next step reaction.
The data of products therefrom being carried out to nuclear-magnetism test are as follows:
1h NMR (400MHz, CDCl
3) δ 3.57 (d, J=10.8Hz, 6H), 3.40 (m, 1H), 3.24 (m, 1H), 1.70-1.44 (m, 4H), 1.43-1.21 (m, 5H), 1.13 (m, 5H), 0.72 (m, 3H).
Embodiment 2
The DMF of compound 3 (1eq) (10vol) solution is cooled to 0 ℃, adds successively imidazoles and TESCl, under room temperature, react 2-3h.Gas phase monitoring reaction finishes, and adds 30mL water will react cancellation.Add 1L water, EA (1L*3) extraction.Organic phase is used respectively saturated NH
4cl (1L), saturated NaHCO
3(1L), Brine (1L) washing once.Dried over mgso, filtration is spin-dried for, and crosses post, obtains target compound 4.Productive rate 88%.
The data of products therefrom being carried out to nuclear-magnetism test are as follows:
1h NMR (400MHz, CDCl
3) δ 3.73 (d, J=10.7Hz, 6H), 3.64 (dd, J=11.3,5.8Hz, 1H), 1.83-1.58 (m, 4H), 1.57-1.46 (m, 2H), 1.45-1.36 (m, 2H), 1.36-1.20 (m, 6H), 0.96 (t, J=7.9Hz, 9H), 0.89 (t, J=7.0Hz, 3H), 0.59 (q, J=8.0Hz, 6H).
Embodiment 3
The DCM of compound 3 (50g, 1eq) (4vol) solution is added to DHP (2eq) and I successively
2, under room temperature, react.Gas phase monitoring reaction finishes, and adds 30mL saturated sodium thiosulfate solution will react cancellation.Add 500mL water, EA (500m*3) extraction.Organic phase is used respectively saturated NH
4cl (1L), saturated NaHCO
3(1L), Brine (1L) washing once.Dried over mgso, filtration is spin-dried for, and crosses post, obtains target compound 5.Productive rate 79%.
The data of products therefrom being carried out to nuclear-magnetism test are as follows:
1h NMR (400MHz, CDCl3) δ 4.62 (dd, J=7.7,4.5Hz, 1H), 3.94-3.84 (m, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.61 (dd, J=7.3,4.1Hz, 1H), 3.49 (dd, J=10.8,5.7Hz, 1H), 1.90-1.23 (m, 20H), 0.89 (t, J=6.8Hz, 3H).
Embodiment 4
In there-necked flask, add K
2cO
3(2eq), DMF (10mL), benzyl bromine (1.5eq), 2 (2g, 1eq), N
2protection, 80 ℃ are stirred 30h, after washing, cross post after extraction, obtain 1.8g, productive rate 46%.
The data of products therefrom being carried out to nuclear-magnetism test are as follows:
1h NMR (400MHz, CDCl3) δ 7.38-7.14 (m, 5H), 5.80-5.58 (m, 1H), 5.13-4.93 (m, 4H), 4.77-4.60 (m, 1H), (2.29 t, J=6.4Hz, 2H), 1.63-1.41 (m, 2H), 1.35-1.10 (m, 6H), 0.89-0.71 (m, 3H).
Embodiment 5
In room temperature downhill reaction bottle, add successively 6 (300mg, 1eq), Isosorbide-5-Nitrae-dioxane, HOP (OMe)
2(5eq), (PhCOO)
2(0.3eq), oil bath is heated to 80 ℃ of reaction 4h, and TLC detects, and raw material reaction is complete, and the cooling rear post of directly crossing, obtains product 190mg product 8, productive rate: 45%.
The data of products therefrom being carried out to nuclear-magnetism test are as follows:
1h NMR (400MHz, CDCl3) δ 7.50-7.26 (m, 5H), 5.15 (s, 2H), 4.78-4.66 (m, 1H), 3.72 (d, J=10.8Hz, 6H), 1.85-1.46 (m, 8H), 1.28 (d, J=6.8Hz, 6H), 0.87 (t, J=6.5Hz, 3H).
Embodiment 6
The DMF of compound 2 (1eq) (10vol) solution is cooled to 0 ℃, adds successively imidazoles and TESCl, under room temperature, react 2-3h.Gas phase monitoring reaction finishes, and adds 30mL water will react cancellation.Add 1L water, EA (1L*3) extraction.Organic phase is used respectively saturated NH
4cl (1L), saturated NaHCO
3(1L), Brine (1L) washing once.Dried over mgso, filtration is spin-dried for, and crosses post, obtains target compound 9.Productive rate 92%.
Above the present invention is described in detail; its object is to allow the personage who is familiar with this art can understand content of the present invention and be implemented; can not limit the scope of the invention with this; the equivalence that all spirit according to the present invention are done changes or modifies, and all should be encompassed in protection scope of the present invention.
Claims (11)
1. a preparation method for the aliphatic phosphate ester of optically active hydroxyl protection, comprises step successively:
(a) addition of phosphoric acid ester unsaturated link(age): phosphoric acid ester is carried out addition to the unsaturated link(age) of compound 2 under the effect of catalyzer, obtains product 3,
(b) hydroxyl of product 3 is protected, is obtained the target compound 1 that skeleton is identical,
2. a preparation method for the aliphatic phosphate ester of optically active hydroxyl protection, comprises step successively:
(a) hydroxyl of compound 2 is protected, is obtained compound 4,
(b) further the carrying out addition reaction with phosphoric acid ester containing the compound 4 of unsaturated link(age) and obtain target compound 1 of hydroxyl protection,
3. the preparation method of the aliphatic phosphate ester of optically active hydroxyl protection according to claim 1 and 2, is characterized in that: starting raw material is that end is with the chiral alcohol of the S-configuration of two keys.
4. the preparation method of the aliphatic phosphate ester of optically active hydroxyl protection according to claim 1 and 2; it is characterized in that: unsaturated link(age) is two keys; phosphoric acid ester comprises benzoyl peroxide to the addition reaction of two keys catalyzer used; dilauroyl peroxide; di-tert-butyl peroxide or dicumyl peroxide, the 0.05-0.3 equivalent that consumption is reaction substrate.
5. the preparation method of the aliphatic phosphate ester of optically active hydroxyl protection according to claim 1 and 2; it is characterized in that: unsaturated link(age) is two keys; phosphoric acid ester is dimethylphosphite to the addition reaction of two keys phosphoric acid ester used, diethyl phosphite or diphenylphosphine oxygen or analogue.
6. the preparation method of the aliphatic phosphate ester of optically active hydroxyl protection according to claim 1 and 2; it is characterized in that: unsaturated link(age) is two keys, and phosphoric acid ester adopts solvent Isosorbide-5-Nitrae-dioxane, DMF or normal heptane to the addition reaction of two keys; preferred solvent is Isosorbide-5-Nitrae-dioxane.
7. the preparation method of the aliphatic phosphate ester of optically active hydroxyl protection according to claim 1 and 2, is characterized in that: unsaturated link(age) is two keys, and phosphoric acid ester comprises and is heated to 50 ℃-100 ℃ the reaction conditions of the addition reaction of two keys.
8. the preparation method of the aliphatic phosphate ester of optically active hydroxyl protection according to claim 1 and 2, is characterized in that: the protection strategy that the protection of hydroxyl adopts, comprise by silicon ether, and ether, ester or carbonic ether are protected.
9. the preparation method of the aliphatic phosphate ester of optically active hydroxyl protection according to claim 1 and 2, is characterized in that: the protective reaction to hydroxyl, and protecting group is TESCl, and the condition of reaction be take imidazoles as alkali, and DMF is solvent.
10. the preparation method of the aliphatic phosphate ester of optically active hydroxyl protection according to claim 1 and 2, is characterized in that: the protective reaction to hydroxyl, and blocking group is THP, catalyzer is I
2, methylene dichloride is solvent, DHP consumption is at 1-10.
The preparation method of the aliphatic phosphate ester of 11. optically active hydroxyl protections according to claim 1 and 2, is characterized in that: the protective reaction to hydroxyl, protecting group is Cbz, under alkali exists with benzyl halide reaction.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9505704B2 (en) | 2014-12-01 | 2016-11-29 | Everlight Chemical Industrial Corporation | Intermediate for synthesizing treprostinil diethanolamine and method for preparing the same |
| CN115010756A (en) * | 2022-07-08 | 2022-09-06 | 江西省科学院应用化学研究所 | Synthetic method of indole organic phosphine compound |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101343289A (en) * | 2008-08-25 | 2009-01-14 | 苏州大学 | Method for synthesis of organo-phosphines acid ester derivant |
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2014
- 2014-01-06 CN CN201410004195.7A patent/CN103709194B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101343289A (en) * | 2008-08-25 | 2009-01-14 | 苏州大学 | Method for synthesis of organo-phosphines acid ester derivant |
Non-Patent Citations (1)
| Title |
|---|
| LI-BIAO HAN ET AL: "Stereospecific Addition of H-P Bond to Alkenes: A Simple Method for the Preparation of (Rp)-Phenylphosphinates", 《J.ORG.CHEM.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9505704B2 (en) | 2014-12-01 | 2016-11-29 | Everlight Chemical Industrial Corporation | Intermediate for synthesizing treprostinil diethanolamine and method for preparing the same |
| CN115010756A (en) * | 2022-07-08 | 2022-09-06 | 江西省科学院应用化学研究所 | Synthetic method of indole organic phosphine compound |
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